i(3)so3-galactosylceramide and Intellectual-Disability

Topics: Animals; Animals, Newborn; Brain; Brain Stem; Cerebellum; Cerebral Cortex; Cerebrosides; Child Development; Cholesterol; DNA; Female; Fetal Diseases; Gangliosides; Guinea Pigs; Humans; Infant Nutrition Disorders; Infant, Newborn; Intellectual Disability; Intelligence; Myelin Sheath; Nutrition Disorders; Organ Size; Phospholipids; Pregnancy; Rats; Sulfoglycosphingolipids

Topics: Brain; Carbohydrate Metabolism, Inborn Errors; Chemical Phenomena; Chemistry; Child; Child, Preschool; Fucose; Gangliosides; Glycosaminoglycans; Humans; Infant; Intellectual Disability; Mannose; Mucopolysaccharidoses; Sphingolipids; Sulfoglycosphingolipids

Progressive epilepsy with mental retardation, EPMR, belongs to a group of inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The CLN8 gene that underlies EPMR encodes a novel transmembrane protein that localizes to the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment. Recently, CLN8 was linked to a large eukaryotic protein family of TLC (TRAM, Lag1, CLN8) domain homologues with postulated functions in lipid synthesis, transport or sensing. By using liquid chromatography/mass spectrometry we analysed molecular species of major phosholipid and simple sphingolipid classes from cerebral samples of two EPMR patients representing a progressive and advanced state of the disease. The progressive state brain showed reduced levels of ceramide, galactosyl- and lactosylceramide and sulfatide as well as a decrease in long fatty acyl chain containing molecular species within these classes. Among glycerophospholipid classes, an increase in species containing polyunsaturated acyl chains was detected especially in phosphatidylserines and phosphatidylethanolamines. By contrast, saturated and monounsaturated species were overrepresented among phosphatidylserine, phosphatidylethanolamine and phosphatidylinositol classes in the advanced state sample. The observed changes in brain sphingo- and phospholipid molecular profiles may result in altered membrane stability, lipid peroxidation, vesicular trafficking or neurotransmission and thus may contribute to the progression of the molecular pathogenesis of EPMR.

Topics: Adult; Aged; Antigens, CD; Brain; Cholesterol; Epilepsy; Galactosylceramides; Humans; Intellectual Disability; Lactosylceramides; Male; Mass Spectrometry; Membrane Proteins; Middle Aged; Neuronal Ceroid-Lipofuscinoses; Neutral Glycosphingolipids; Phosphatidylethanolamines; Phosphatidylserines; Sphingomyelins; Sulfoglycosphingolipids

Metachromatic leukodystrophy (MLD) is a disease caused by a deficiency of the enzyme sulfatide sulfatase, also known as arylsulfatase A (ASA). We compared the activity of this enzyme in adult psychiatric patients and normal volunteers using nitrocatechol sulfate (ASA-NCS) and cerebroside sulfate (ASA-CS) as substrates. Our results showed that ASA-NCS activity in urine and leukocytes was significantly lower in psychiatric than in normal individuals, but that there were no differences between these two groups in the sulfatide excretion in urine or the ASA-CS activity in leukocytes. There was no correlation between enzyme activity in urine and in leukocytes, indicating that activity in urine does not truly reflect the levels of the enzyme in tissues. The correlation between ASA-NCS and ASA-CS activity in leukocytes was poor (0.51 for psychiatric patients and 0.59 for normals), suggesting that for a valid measure of the enzyme activity the assays should be carried out with CS as substrate. Results of our study also indicate that in 39 of the 145 psychiatric patients studied, the ASA-CS activity in leukocyte was less than 4 nmoles/mg protein/hr, which is below 50% of the normal means, whereas only one of the 30 normal subjects had a value this low. The presence of low levels of ASA-CS activity in a significantly large number of adult patients with varying psychiatric manifestations suggests that such patients may be asymptomatic carriers of the sulfatidase defect (heterozygotes for MLD), and that behavioral and functional disturbances in these patients may at least in part be related to sulfatidase deficiency. The significance of the ASA-NCS abnormality (reduction) in psychiatric patients is unclear.

Topics: Cerebroside-Sulfatase; Female; Humans; Huntington Disease; Intellectual Disability; Leukocytes; Leukodystrophy, Metachromatic; Male; Mental Disorders; Neurocognitive Disorders; Schizophrenia; Sulfatases; Sulfoglycosphingolipids

A woman aged 21 with a variant form of metachromatic leucodystrophy (MLD) combined with another form of leucodystrophy is described. The clinical symptoms were retinitis pigmentosa and progressive neurological deficits such as mental retardation, dystonia, pyramidal tract involvement and peripheral neuropathy. The biochemical findings were marked deficiency of arylsulfatase-A and cerebroside-sulfatase in cultured fibroblasts and excretion of sulfatides in the urine. Sulfatide-loading of cultured fibroblasts showed almost normal uptake and degradation of sulfatides. The patient's sister suffers from a clinically similar neurological disease, but normal activity of arylsulfatase-A was found in her leucocytes. A severe oral-facial dystonia in the patient was successfully controlled by l-dopa.

Topics: Adult; Central Nervous System Diseases; Cerebroside-Sulfatase; Female; Fibroblasts; Humans; Intellectual Disability; Leukocytes; Leukodystrophy, Metachromatic; Nerve Degeneration; Neuromuscular Diseases; Retinitis Pigmentosa; Sulfoglycosphingolipids

We compared the sphingolipid content of urine from a patient with Farber's disease with that of control urine. The ceramides were measured by high-performance liquid chromatography. The patient's urine contained 1.2 mug of ceramides per milligram of creatinine, more than 200-fold the normal amount. The urinary ceramides were isolated by high-performance liquid chromatography for further identification. They contained mainly nonhydroxy fatty acids and only a small quantity of those with 2-hydroxy fatty acids. This contrasts with the previously described composition of the patient's renal and cerebellar tissue. The fatty acid and long-chain base compositions of the urinary ceramides containing nonhydroxy fatty acids were nearly identical to those of the patient's kidney.

Topics: Ceramides; Cerebrosides; Cholesterol; Chromatography; Fatty Alcohols; Humans; Intellectual Disability; Kidney; Leukodystrophy, Metachromatic; Lipidoses; Lipids; Male; Pigmentation Disorders; Spectrophotometry, Infrared; Sphingomyelins; Sulfoglycosphingolipids

Topics: Child; Diffuse Cerebral Sclerosis of Schilder; Eye Manifestations; Gangliosides; Humans; Infant, Newborn; Intellectual Disability; Lipid Metabolism, Inborn Errors; Lipidoses; Lipopolysaccharides; Macula Lutea; Male; Niemann-Pick Diseases; Pigmentation Disorders; Respiratory Distress Syndrome, Newborn; Sphingolipids; Sphingomyelins; Sulfoglycosphingolipids; Syndrome